PROJECT SUMMARY Individuals who experience a nonfatal opioid overdose (OD) are known to be at exceedingly high risk of dying from a subsequent OD, but effective secondary OD prevention interventions are lacking. Most people who have an OD are brought to an emergency department (ED). ED visits thus offer a unique opportunity to reach those at highest risk for future OD death. In response, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) has implemented Relay, a novel program that engages and intervenes with individuals in the ED following an opioid OD and for the next 90 days, with the goal of preventing subsequent OD events. The Relay intervention is grounded in the theory of triadic influence and dynamic social impact theory, and it incorporates a motivational approach. Relay is delivered by trained peer navigators, who are DOHMH staff with lived substance use experience. The proposed randomized controlled trial represents a collaboration between academic, public health, and medical service partners to evaluate the impact of Relay on preventing subsequent opioid-related adverse events. A total of 350 eligible individuals with nonfatal opioid OD presenting to one of 4 participating EDs will be enrolled and randomized to one of two arms: 1) enhanced usual care (EUC)?OD education and naloxone distribution (OEND) and list of opioid treatment programs; or 2) Relay?peer-delivered OD education and treatment linkage, including 90 days of peer navigation. Outcomes will be measured for 12 months through interviews and administrative health data. Aim 1 is to evaluate the effectiveness of Relay to reduce the frequency of opioid-related adverse events (any opioid-involved OD [fatal or nonfatal] or any substance use-related ED visit), in the 12 months following the index visit, the primary outcome. Aim 2 is to evaluate the impact of Relay on the following secondary outcomes: initiation of medication for opioid use disorder (MOUD), OD risk behaviors, time to next opioid-involved OD, and frequency of ED visits for any cause. Aim 3 is to identify mediators (e.g., OD knowledge, support, experience of stigma, peer modeling) and moderators (e.g., substance use history, age, sex, housing status) of the effect of Relay. Aim 4 is to evaluate Relay?s implementation by assessing fidelity to the program model and exploring barriers and facilitators to its delivery and sustainability through qualitative interviews with patients, Relay peer navigators, and ED providers. The proposed study is significant because it will provide rigorous evidence about whether peer interventions like Relay can meaningfully impact the opioid crisis by reducing opioid- related adverse events. In the midst of an opioid crisis that shows no signs of abating, health authorities are developing programs aimed at reducing OD deaths, even in the absence of strong evidence to support them. This is a critically important time to conduct research that identifies which of these new approaches are effective, and under what conditions, so they can be brought to scale to improve population health.